Junyan Li

Common Variants in Major Histocompatibility Complex Region and TCF4 Gene Are Significantly Associated with Schizophrenia in Han Chinese

BACKGROUND Schizophrenia is a complex major psychiatric disorder affecting ∼1% of the world population. Recently, in a genome-wide association study and a follow-up in Caucasians, Stefansson et al. examined 7662 schizophrenic cases and 29053 normal control subjects and reported seven common single nucleotide polymorphisms (SNPs) that were significantly (>10(-8)) associated with schizophrenia. METHODS To investigate whether these risk SNPs were significantly associated in Han Chinese, we analyzed the seven SNPs in 2496 schizophrenia patients and 5184 normal control subjects. Because only three of the seven SNPs were polymorphic in Han Chinese, we genotyped two additional common SNPs from the same risk regions. RESULTS Three SNPs, rs6932590 (p = .00096), rs3131296 (p = 1.29 × 10(-6)), and rs3130375 (p = 1.76 × 10(-5)), mapping to the major histocompatibility complex region and one SNP rs2958182 (p = 3.64 × 10(-6)) located in the TCF4 gene were significant in our sample set. A meta-analysis using published genome-wide association study results also supported our findings. CONCLUSIONS Our results confirm that common risk factors in the major histocompatibility complex region and TCF4 gene are associated with schizophrenia in Han Chinese, but our results fail to show an association with SNP rs12807809 in the NRGN gene.

A genome-wide association study reveals association between common variants in an intergenic region of 4q25 and high-grade myopia in the Chinese Han population

High-grade myopia (HM) is highly heritable, and has a high prevalence in the Han Chinese population. We carried out a genome-wide association study involving 102 HM cases suffering from retinal degeneration, and 335 controls who were free from HM and fundus diseases. Significant single-nucleotide polymorphisms were replicated in two follow-up studies: stage I involved 2628 independent cases and 9485 controls, and stage II involved a further 263 cases and 586 HM-free controls. The results were combined in a meta-analysis. Cases and controls were drawn from the Chinese Han population. A locus in an intergenic region at 4q25, within MYP11 (4q22-q27, OMIM: 609994), was found to be associated with HM (rs10034228, P(meta) = 7.70 × 10(-13), allelic odds ratio = 0.81, 95% confidence interval 0.76-0.86). There are no known genes in the region but a number of expressed sequence tags (ESTs) have been located there, one of which (BI480957) has been reported to express in the native human retinal pigment epithelium. In addition, a predicted gene was identified in this region. The genes predicted protein sequence is highly similar to tubulin, beta 8 and beta-tubulin 4Q. Several previous studies have shown that tubulin plays an important role in eye development. Our result is compatible with a previous linkage study in the Han Chinese population (mapping in MYP11, 4q22-q27), and provides a more accurate locus for HM. Although there is insufficient evidence to indicate that expressed EST and the predicted gene play an important role in developing HM, this region merits further study as a candidate for the disease.

Association of genetic polymorphisms in the type II deiodinase gene with bipolar disorder in a subset of Chinese population.

OBJECTIVE Genetic factors play a critical role in the etiology of bipolar disorder (BPAD). Previous studies suggested an association between thyroid dysfunction and BPAD. We hypothesize that genetic variations in the type II deiodinase (DIO2) gene that possibly alter the bioactivity of thyroid hormones are associated with BPAD. METHOD A case-control association study was conducted in a subset of Chinese Han population. Two single nucleotide polymorphisms (SNP), open reading frame a (ORFa)-Gly3Asp (rs12885300) and Thr92Ala (rs225014) with potential functions on the activity of DIO2, were selected. The frequencies of allele, genotype and haplotype of the two SNPs were compared between the BPAD patients and the control group. RESULTS Statistical significance between the BPAD patients and the control group was observed for the allele (chi(2)=7.746, P=0.005, df=1) and genotype frequencies (chi(2)=8.158, P=0.017, df=2) at the locus of ORFa-Gly3Asp, and for the allele (chi(2)=15.838, P=7.00e-005, df=1) and genotype frequencies (chi(2)=17.236, P=0.0002, df=2) at Thr92Ala. Distribution of allele 3Gly and 92Ala were significantly higher in the BPAD patients, with odds ratios of 1.489 [95% confidence interval (CI)=1.124-1.973] and 1.616 [95% CI=1.275-2.048], respectively. Individuals with two copies of the variant 3Gly or 92Ala were at greater risk of BPAD than individuals with one copy (dose-response manner). Haplotypes ORFa-3Asp-92Ala and ORFa-3Gly-92Ala indicated higher susceptibility for BPAD with odds ratios of 3.759 (95% CI=2.013-7.020) and 1.292 (95% CI=1.017-1.642), respectively, while ORFa-3Asp-92Thr probably played a protective role with an odds ratio of 0.395 (95% CI=0.284-0.549). CONCLUSION Data generated from this study supported our hypothesis that genetic variations of the DIO2 gene were associated with BPAD and suggested further consideration on the possible involvement of these functionally active variants in the pathophysiology of BPAD.

Common variants in the BCL9 gene conferring risk of schizophrenia.

CONTEXT Recent genome-wide association studies have revealed that common variations and rare copy-number variations contribute to the risk of mental disorders. Rare recurrent microdeletions at 1q21.1 were reported to be associated with schizophrenia, and the BCL9 gene at 1q21.1 was also a functional candidate gene for mental disorders. OBJECTIVES To investigate and validate whether common variations exist in a functional candidate gene in the copy-number variation region, and, if so, to determine whether these variations confer risk of schizophrenia or other mental disorders. DESIGN A 3-stage case-control study. SETTING Shanghai, China. PARTICIPANTS A total of 12 229 subjects were included: 5772 normal controls, 4187 patients with schizophrenia, 1135 patients with bipolar disorder patients, and 1135 patients with major depressive disorder. Main Outcome Measure During the first and second stages of our study, we genotyped 10 single-nucleotide polymorphisms using the ligation detection reaction method. During the third stage of our study, all single-nucleotide polymorphisms were genotyped using TaqMan technology (Applied Biosystems, Foster City, California). RESULTS During the first stage of our study, we found that rs672607 was significantly associated with schizophrenia (P = 2.69 × 10(-5)). During the second stage, rs672607 was successfully replicated (P = 1.33 × 10(-5)), and rs9326555 (P = .002), rs1240083 (P = 1.7 × 10(-4)), and rs688325 (P = .006) were newly identified to be significant. During the third stage, we genotyped all single-nucleotide polymorphisms in 1135 patients with schizophrenia, 1135 patients with bipolar disorder, 1135 patients with major depressive disorder, and 1135 normal controls for further validation. Finally, when we combined all the data from the 3 stages of our schizophrenia study, we found that rs9326555 (P = 1.53 × 10(-5)), rs10494251 (P = .02), rs1240083 (P = 1.52 × 10(-4)), rs672607 (P = 1.23 × 10(-11)), rs688325 (P = 2.54 × 10(-4)), and rs3766512 (P = .01) were significant. Moreover, we found that rs672607 was significant in major depressive disorder (P = .001) and bipolar disorder (P = .03), and rs10494251 (P = .04), rs1541187 (P = .04), rs688325 (P = .02), and rs946903 (P = .006) were significant in major depressive disorder. CONCLUSION These findings indicate that common variations in the BCL9 gene confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder in the Chinese Han population.

The Endothelial Nitric Oxide Synthase Gene Is Associated with Coronary Artery Disease: A Meta-Analysis

Introduction: Previous case-control studies have suggested that the endothelial nitric oxide synthase (eNOS) gene polymorphisms (G894T, 4b/a, T-786C) are associated with coronary artery disease (CAD). However, other studies do not confirm these relationships. The objective was to assess these relationships using meta-analysis. Methods: Databases, including Pubmed and Embase, were searched to access the relevant genetic association studies up to July 2009. Results: The meta-analysis included 56 studies, consisting of 23 studies for G894T, 19 for 4b/a and 14 for T-786C. For the allelic analysis of the G894T variant, all studies showed a positively significant association (OR = 0.83, p = 0.004). For the genotypic analysis, the combined studies of the T allele showed significance (OR = 1.57, p = 0.003). For the allelic analysis of the T-786C variant, all studies showed an obviously significant association (OR = 0.79, p = 0.0007), reflected in both non-Asian and Asian studies. For the genotype analysis, combined studies of the C allele showed significance (OR = 0.72, p = 0.0001). Moreover, non-Asian studies showed significant results. For the analysis of the 4b/a variant, none of the studies showed significant results. No publication bias was found in the meta-analysis. Conclusion: The synthesis of available evidence supports the fact that eNOS G894T andT-786C are associated with CAD.

FoxP2 is significantly associated with schizophrenia and major depression in the Chinese Han Population

Abstract Objectives. The FoxP2 gene, located on 7q31, encodes a transcription factor. It was first discovered through investigations of a large multigenerational family (the KE family) with a rare severe speech and language disorder (Fisher et al., Nat. Genet. 1998;18:168; Lai et al., Nature 2001;413:519). Subsequent studies gave powerful and convincing functional evidence to the connection between FoxP2 and language disorder (; Groszer et al., Curr Biol 2008;18:354; Vernes et al., New Engl J Med 359(22):2337). Language disorder is commonly considered as a core symptom of schizophrenia and some other mental diseases; thus, we decided to investigate whether the FoxP2 gene played a significant role in schizophrenia, major depression or bipolar disorder in a sample set recruited from the Chinese Han population. Methods. In this study, we focused on 12 SNPs in the FoxP2 gene and carried out case–control studies in 1135 schizophrenia patients, 1135 unrelated major depression patients, 1135 unrelated bipolar disorder patients and 1135 unrelated normal controls recruited from the Chinese Han population. Results. We found rs10447760 was significantly associated with schizophrenia (allelic P = 0.00069) and major depression (allelic P = 0.0011). Conclusions. Our study indicated that the rare variant rs10447760 in FoxP2 may play an important role in schizophrenia and major depression in the Chinese Han population.

The MDGA1 gene confers risk to schizophrenia and bipolar disorder

OBJECTIVE The structural, cytoarchitectural and functional brain abnormalities reported in patients with mental disorders may be due to aberrant neuronal migration influenced by cell adhesion molecules. MDGA1, like Ig-containing cell adhesion molecules, has several cell adhesion molecule-like domains. Moreover, Kahler et al. (2008) reported that the MDGA1 gene was a schizophrenia susceptibility gene in Scandinavian population. To further investigate whether the MDGA1 gene is a shared risk factor of schizophrenia, bipolar disorder and major depressive disorder in Chinese Han population, we conducted this study. METHODS We recruited 1135 unrelated schizophrenia patients, 1135 unrelated bipolar disorder patients, 1135 unrelated major depressive disorder patients and 1135 unrelated controls of Chinese Han origin. A total of eleven common SNPs were genotyped using TaqMan® technology. RESULTS The genotype frequency of rs11759115 differed significantly between schizophrenia patients and controls. The C-C haplotype of rs11759115-rs7769372 was also positively associated with schizophrenia (permutated p=0.046). Rs1883901 was found to be positively associated with bipolar disorder (allele: permutated p=0.0085; genotype: permutated p=0.0009; OR=1.31 [95%CI=1.12-1.52]). The A-G-G haplotype of rs1883901-rs10807187-rs9462343 was also positively associated with bipolar disorder with a global p value of 0.0391 after permutations. No individual SNP or haplotype was associated with major depressive disorder after permutations. CONCLUSION The MDGA1 gene may confer risk to schizophrenia and bipolar disorder in Chinese Han population.

Common SNPs in Myelin Transcription Factor 1-Like (MYT1L): Association with Major Depressive Disorder in the Chinese Han Population

Background Myelin transcription factor 1-like (MYT1L) is a member of the myelin transcription factor 1 (MYT1) gene family, and the neural specific, zinc-finger-containing, DNA-binding protein that it encodes plays a role in the development of the nervous system. On the basis of a recent copy number variation (CNV) study showing that this gene is disrupted in mental disorder patients, we investigated whether MYT1L also plays a role in MDD. Methods In this study, 8 SNPs were analyzed in 1139 MDD patients and 1140 controls of Chinese Han origin. Results Statistically significant differences were noted between cases and controls for rs3748989 (allele: permutated p = 0.0079, corrected p = 0.0048, genotype: corrected p = 0.0204). A haplotype of rs1617213 and rs6759709 G-C was also significant (permutated p = 0.00007). Conclusion Our results indicate that MYT1L may be a potential risk gene for MDD in the Chinese Han population.

CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population.

Previous studies have reported that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene, which is related to immunological function such as T-cell regulation, is associated with psychiatric disorders. In this study, we studied the relationship between CTLA-4 and three major psychiatric disorders, schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han population. We recruited 1140 schizophrenia patients, 1140 major depressive disorder patients, 1140 bipolar disorder patients, and 1140 normal controls to examine the risk conferred by 6 tag SNPs (rs231777, rs231775, rs231779, rs3087243, rs5742909, rs16840252) in the CTLA-4 gene. We found that rs231779 conferred a risk for schizophrenia (P(allele)=0.0003, P(genotype)=0.0016), major depressive disorder (P(allele)=0.0006, P(genotype)=0.0026) and bipolar disorder (P(allele)=0.0004, P(genotype)=0.0018). In addition, rs231777 and rs16840252 had a significant association with schizophrenia (rs231777: P(allele)=0.0201, rs16840252: P(allele)=0.0081, P(genotype)=0.0117), and rs231777 had significant association with bipolar disorder (rs231777: P(allele)=0.0199). However, after 10,000 permutations, only rs231779 remained significant (schizophrenia: P(allele)=0.0010, P(genotype)=0.0145, major depressive disorder: P(allele)=0.0010, P(genotype)=0.0201, bipolar disorder: P(allele)=0.0008, P(genotype)=0.0125). Our results suggest that shared common risk factors for schizophrenia, major depressive disorder and bipolar disorder exist in the CTLA-4 gene in the Chinese Han population.

Polymorphisms and Haplotypes in the YWHAE Gene Increase Susceptibility to Bipolar Disorder in Chinese Han Population

BACKGROUND Schizophrenia and bipolar disorder are 2 major psychiatric illnesses sharing some specific genetic risk factors. Increasing evidence suggests the 2 illnesses might be more closely related than previously considered. OBJECTIVE To test this hypothesis, we investigated the allele and genotype frequencies of 11 single nucleotide polymorphisms (SNPs) and the haplotypes in these SNPs of the YWHAE gene. METHOD 1,982 patients were interviewed by 2 independent, experienced psychiatrists. Bipolar disorder diagnoses were made in strict accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria using the Structured Clinical Interview for DSM-IV Axis I Disorders. In 2011, we conducted this genetic association analysis between 11 SNPs in YWHAE and bipolar disorder, involving a male group and a female group. RESULTS In the analysis of allele and genotype frequencies, the SNP rs1873827 increased susceptibility to bipolar disorder in the male group. The haplotype analysis of CAC in rs3752826, rs2131431, and rs1873827 in the male group (χ2 = 25.744, P = 3.97E-07, OR = 0.478 [95% CI, 0.358-0.639]) and of ACT and CAC in rs3752826, rs2131431, and rs1873827 in the female group (for ACT, χ2 = 30.365, P = 3.67E-08, OR = 0.040 [95% CI, 0.007-0.218]; for CAC, χ2 = 16.874, P = 4.04E-05, OR = 0.597 [95% CI, 0.466-0.765]) showed they are protective factors for bipolar disorder. However, the haplotype analysis of CAT in the male group (χ2 = 19.874, P = 8.39E-06, OR = 2.314 [95% CI, 1.587-3.374]) and of AAC and CAT in the female group (for AAC, χ2 = 38.561, P = 5.47E-10, OR = 7.104 [95% CI, 3.471-14.540]; for CAT, χ2 = 25.497, P = 4.52E-07, OR = 2.076 [95% CI, 1.556-2.770]) showed they are risk factors for bipolar disorder. CONCLUSIONS Considering the size of our sample, the results suggest that YWHAE does play a major role in bipolar disorder in the Han Chinese population.